This project proposes to systematically study relationships between thymoleptic properties of tricyclic antidepressants and their side chain conformations. To this end a large number of rigid structures will be synthesized wherein the side chains are held in various fixed conformations. Ring fusion isomers will be separated by chromatographic techniques and their structures confirmed by X-ray crystallography, nuclear magnetic resonance and/or circular dichroism. The target compounds will be evaluated for antidepressant activities in experimental animals, for inhibition of norepinephrine and serotonin uptake, and for central anticholinergic activity in vitro and in vivo.